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Transplantation of live cells as therapeutic agents is poised to offer new treatment options for a wide range of acute and chronic diseases. However, the biological complexity of cells has hampered the translation of laboratory-scale experiments into industrial processes for reliable, cost-effective manufacturing of cell-based therapies. We argue here that a solution to this challenge is to design cell manufacturing processes according to quality-by-design (QbD) principles. QbD integrates scientific knowledge and risk analysis into manufacturing process development and is already being adopted by the biopharmaceutical industry. Many opportunities to incorporate QbD into cell therapy manufacturing exist, although further technology development is required for full implementation. Linking measurable molecular and cellular characteristics of a cell population to final product quality through QbD is a crucial step in realizing the potential for cell therapies to transform healthcare.

Use of clinical-grade human induced pluripotent stem cell (iPSC) lines as a starting material for the generation of cellular therapeutics requires demonstration of comparability of lines derived from different individuals and in different facilities. This requires agreement on the critical quality attributes of such lines and the assays that should be used. Working from established recommendations and guidance from the International Stem Cell Banking Initiative for human embryonic stem cell banking, and concentrating on those issues more relevant to iPSCs, a series of consensus workshops has made initial recommendations on the minimum dataset required to consider an iPSC line of clinical grade, which are outlined in this report. Continued evolution of this field will likely lead to revision of these guidelines on a regular basis.

Due to their self-renewal capacity, multilineage differentiation potential, paracrine effects, and immunosuppressive properties, mesenchymal stromal cells (MSCs) are an attractive and promising tool for regenerative medicine. MSCs can be isolated from various tissues but despite their common immunophenotypic characteristics and functional properties, source-dependent differences in MSCs properties have recently emerged and lead to different clinical applications. Considered for a long time as a medical waste, umbilical cord appears these days as a promising source of MSCs. Several reports have shown that umbilical cord-derived MSCs are more primitive, proliferative, and immunosuppressive than their adult counterparts. In this review, we aim at synthesizing the differences between umbilical cord MSCs and MSCs from other sources (bone marrow, adipose tissue, periodontal ligament, dental pulp,…) with regard to their proliferation capacity, proteic and transcriptomic profiles, and their secretome involved in their regenerative, homing, and immunomodulatory capacities. Although umbilical cord MSCs are until now not particularly used as an MSC source in clinical practice, accumulating evidence shows that they may have a therapeutic advantage to treat several diseases, especially autoimmune and neurodegenerative diseases.

Regulatory cell therapies, including regulatory T cells and mesenchymal stromal cells, have shown promise in early clinical trials for reducing immunosuppression burden in transplantation. While regulatory cell therapies may also offer potential for treating autoimmune kidney diseases, data remains sparse, limited mainly to preclinical studies. This review synthesises current literature on the application of regulatory cell therapies in these fields, highlighting the safety and efficacy shown in existing clinical trials. We discuss the need for further clinical validation, optimisation of clinical and immune monitoring protocols, and the challenges of manufacturing and quality control under Good Manufacturing Practice conditions, particularly for investigator-led trials. Additionally, we explore the potential for expanding clinical indications and the unique challenges posed in paediatric applications. Future directions include scaling up production, refining protocols to ensure consistent quality across manufacturing sites, and extending applications to other immune-mediated diseases. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

We report on manufacturing outcomes for 41 autologous polyclonal regulatory T cell (PolyTreg) products for 7 different Phase 1 clinical trials over a 10-year period (2011-2020). Data on patient characteristics, manufacturing parameters, and manufacturing outcomes were collected from manufacturing batch records and entered into a secure database. Overall, 88% (36/41) of PolyTreg products met release criteria and 83% (34/41) of products were successfully infused into patients. Of the 7 not infused, 5 failed release criteria, and 2 were not infused because the patient became ineligible due to a change in clinical status. The median fold expansion over the 14-day manufacturing process was 434.8 -fold (range 29.8-2,232), resulting in a median post-expansion cell count of 1,841 x 10 6 (range 56.9-16,179 x 10 6 ). The main correlate of post-expansion cell number was starting cell number, which positively correlates with absolute circulating Treg cell count. Other parameters, including date of PolyTreg production, patient sex, and patient age did not significantly correlate with fold expansion of Treg during product manufacturing. In conclusion, PolyTreg manufacturing outcomes are consistent across trials and dates of production.

A number of immune regulatory cellular therapies, including regulatory T cells and mesenchymal stromal cells, have emerged as novel alternative therapies for the control of transplant alloresponses. Clinical studies have demonstrated their feasibility and safety, however developing our understanding of the impact of cellular therapeutics in vivo requires advanced immune monitoring strategies. To accurately monitor the immune response, a combination of complementary methods is required to measure the cellular and molecular phenotype as well as the function of cells involved. In this review we focus on the current immune monitoring strategies and discuss which methods may be utilized in the future.

Regenerative medicine is a rapidly evolving field of contemporary biomedical research that offers new therapeutic strategies for conditions previously considered untreatable. Cell therapy shows particular potential in this domain. However, rigorous biosafety measures are required in its development and clinical application. This review proposes a practice-oriented biosafety framework for cell therapy, translating key risks into operational principles: toxicity, oncogenicity/tumorigenicity/teratogenicity, immunogenicity, biodistribution; and cell product quality. For each principle, preclinical approaches and regulatory expectations are summarized. Criteria for immunological safety are addressed, including activation of innate immunity (complement, T- and NK-cell responses) and the need for HLA typing. Biodistribution assessment involves the use of quantitative PCR and imaging techniques (PET, MRI) to monitor cell fate over time. The risks of oncogenicity, tumorigenicity, and teratogenicity can be analyzed using a combination of in vitro methods and in vivo models in immunocompromised animals. Product quality assessment includes sterility, identity, potency, viability, and genetic stability, with alignment of procedures to regulatory requirements and an emphasis on quality-by-design principles to ensure safe and reproducible clinical use. Integrating toxicity and safety pharmacology data supports a balanced risk–benefit assessment and clinical trial planning.

Hundreds of businesses in the US currently advertise a wide range of non-US FDA-approved stem cell interventions. Here we present a novel systematic temporal analysis of US companies engaged in direct-to-consumer marketing of putative stem cell treatments. Between 2009 and 2014, the number of new US stem cell businesses with websites grew rapidly, at least doubling on average every year. From 2014 to 2016, approximately 90-100 new stem cell business websites appeared per year. In contrast, from 2012 to the present, regulatory activity in the form of FDA warning letters has been limited. These data point to a problematic disconnect between a rapidly expanding US direct-to-consumer stem cell industry and limited FDA oversight of this marketplace. More consistent, timely and effective FDA actions are urgently needed.

Contamination with tumorigenic cellular impurities is one of the most pressing concerns for human cell-processed therapeutic products (hCTPs). The soft agar colony formation (SACF) assay, which is a well-known in vitro assay for the detection of malignant transformed cells, is applicable for the quality assessment of hCTPs. Here we established an image-based screening system for the SACF assay using a high-content cell analyzer termed the digital SACF assay. Dual fluorescence staining of formed colonies and the dissolution of soft agar led to accurate detection of transformed cells with the imaging cytometer. Partitioning a cell sample into multiple wells of culture plates enabled digital readout of the presence of colonies and elevated the sensitivity for their detection. In practice, the digital SACF assay detected impurity levels as low as 0.00001% of the hCTPs, i.e. only one HeLa cell contained in 10,000,000 human mesenchymal stem cells, within 30 days. The digital SACF assay saves time, is more sensitive than in vivo tumorigenicity tests and would be useful for the quality control of hCTPs in the manufacturing process.